Combination Treatment of Influenza A Virus Infections in Cell Culture and in Mice with the Cyclopentane Neuraminidase Inhibitor RWJ-270201 and Ribavirin

Abstract

Treatment of virus infections with compounds acting by different mechanisms may lead to more potent effects when these agents are used in combination. Under this premise, two known active influenza virus inhibitors, ribavirin and the novel cyclopentane influenza virus neuraminidase inhibitor (1S,2S,3R,4R)-3-[(1S)-(acetylamino)-2-ethylbutyl]-4-[(aminoiminomethyl)amino]-2-hydroxy-cyclopentanecarboxylic acid (RWJ-270201, BCX-1812) were studied. Experiments in cell culture demonstrated that RWJ-270201 plus ribavirin synergistically reduced extracellular influenza A/NWS/33 (H1N1) virus yields at low concentrations of each inhibitor. Mice were treated with ribavirin at 20 and 6.25 mg/kg/day combined with RWJ-270201 at 1, 0.32, or 0.1 mg/kg/day, or used alone. Treatments were twice daily for 5 days starting 4 h before exposure to influenza A/NWS virus. Only RWJ-270201 alone at 1 mg/kg/day significantly prevented mortality. In contrast, most drug combinations increased survival significantly compared to the placebo group. Doses of the two compounds used in combination delayed the mean day of death, and improved arterial oxygen saturation levels, as measured on day 11 of the infection. The combination of the two inhibitors produced additive to synergistic interactions in these mouse experiments with no enhancement of host toxicity. Treatment of influenza infections in the clinical setting may benefit by these two agents in combination.

Rimantadine and Oseltamivir Demonstrate Synergistic Combination Effect in an Experimental Infection with Type a (H3N2) Influenza Virus in Mice

“…Peramivir and ribavirin produce an additive to synergistic effect against influenza A virus in vitro and in experimental influenza virus A (H1N1) infection in mice (Smee et al, 2002). Govorkova et al (2004) Leneva et al (2000) …”

Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice

“…The activity of ribavirin alone or in combination with other antiviral agents against highly pathogenic H5N1 viruses has not been studied, but the activity of ribavirin against influenza viruses of the H1N1 and H3N2 subtypes has been investigated in vitro and in vivo (14,18,23,39,40,45). Ribavirin combined with rimantadine or zanamivir exerted an additive antiviral effect and, at specific concentrations, a synergistic antiviral effect to reduce the yield of influenza viruses in Madin-Darby canine kidney (MDCK) cells (14,23).…”

“…In a mouse model, the use of ribavirin with the M2 ion-channel blocker amantadine enhanced the survival of the mice, and the combination was significantly more effective than either drug alone (45). Ribavirin interacted additively and synergistically with the NA inhibitor peramivir to reduce the levels of H1N1 influenza virus infection in vitro and in vivo (23,40).…”

Chemotherapy of Influenza: Current and Novel Approach

“…Further, ribavirin was tested in combination with zanamivir (the first NAI) and rimantadine interacting in an additive fashion against influenza A (H3N2) and (H1N1) virus in MDCK cells and with 2'-deoxy-2'-fluoroguanidine (2-FDG), a nucleoside analogue, it was synergistic against H1N1 subtype (50). Ribavirin plus peramivir showed additive to synergistic effect against influenza A (H1N1) virus in vitro (78). Ribavirin-oseltamivir combination was additively active in vitro against H1N1 and H5N1 (62, 80).…”

“…Ribavirin plus peramivir manifested additive to synergistic effect against influenza A H1N1 virus in experimental infection in mice (78). Combined ribavirin and oseltamivir effects on H1N1 and B were evaluated in mouse model by Smee et al (81) as additive or synergistic, depending on the virus strain and/or the dose of the drugs.…”